LOS ANGELES – Drugmakers and researchers at the American Society of Gene & Cell Therapy's annual meeting from May 16 to 20 reported data on gene therapies they're developing for a variety of rare diseases. Below are brief reports on data readouts shared by researchers.
Pfizer's fordadistrogene movaparvovec
A gene therapy being developed by Pfizer slowed the decline of motor functions in patients with Duchenne muscular dystrophy, according to early results from a Phase Ib trial researchers reported Friday.
In the first-in-human Pfizer-sponsored trial, investigators are testing fordadistrogene movaparvovec, an adeno-associated virus serotype-9 (AAV9) vector-based gene-replacement therapy that contains a truncated DMD transgene. Investigators enrolled 16 ambulatory patients with confirmed genetic diagnoses of DMD, all of whom received a single infusion of the gene therapy.
Perry Shieh, a professor of neurology at the University of California, Los Angeles, presented data on patients' motor function two years after treatment with fordadistrogene movaparvovec. Investigators compared these patients' outcomes with two external control groups with similar characteristics.
The first external control group, Shieh said, was generated with a prediction model using data from large natural history databases. The other was constructed with two-year data from patients in a failed Phase II trial of domagrozumab, an investigational DMD therapy that Pfizer abandoned in 2018.
"This was a negative study, so essentially, there was no treatment effect," Shieh said of the domagrozumab-treated cohort. "This was not truly a natural history or placebo-controlled [cohort], but because of the no treatment effect, it might achieve a similar type of analysis."
The data presented at the ASGCT meeting showed that although motor functions of patients given fordadistrogene movaparvovec continued to decrease after treatment, the rate of decline was slower than those who weren't treated with the gene therapy. Investigators gauged patients' motor functions using the North Star Ambulatory Assessment (NSAA), a 34-point scale, in which 0 represents a patient's inability to act independently and higher scores represent "normal" function.
Based on the analysis by Shieh and colleagues, patients' average motor function decreased by 2.6 points on the NSAA from before treatment to two years after infusion compared to a decrease of 4.9 points for patients in the first external control group and 4.5 points for those in the latter external control group.
"The change two years after dosing varied by age," Shieh noted, with the benefit more pronounced in younger patients.
For patients between 6 and 7 years old, the average change in the motor function score two years after treatment improved by half a point. Comparatively, it decreased by 4.4 points for those between 8 and 12 years old. In the first external control group, younger patients' motor scores over two years on average decreased by 2 points and by 6.7 points in older patients; motor scores decreased by 3.6 points and 4 points, respectively, for patients in the second control group based on age.
There were five serious adverse events observed in patients up to two years after treatment. Three of these cases — dehydration, acute kidney injury, and thrombocytopenia — were deemed treatment-emergent, Shieh said. However, those events resolved within 15 days. Shieh did not discuss the two other serious adverse events reported during the trial.
The US Food and Drug Administration in 2021 instituted a clinical hold on Pfizer's investigational new drug application for fordadistrogene movaparvovec, after a patient in a non-ambulatory cohort of the Phase Ib study experienced a fatal serious adverse event. The FDA lifted the hold in April 2022, at which point Pfizer announced it was starting a Phase III trial of the gene therapy in the US.
Rocket Pharmaceuticals' RP-A501
Results from an ongoing Phase I study presented Thursday have given Rocket Pharmaceuticals reason to move ahead with a planned pivotal Phase II study, in which investigators will continue to assess the company's gene therapy for Danon disease, RP-A501.
"We do see preliminary evidence of efficacy," Joseph Rossano, a principal investigator of the Phase I trial and chief of the cardiology division at Children's Hospital of Philadelphia, said at the conference. "We hope to advance a pivotal global Phase II study."
Rocket expects to begin the Phase II study of RP-A501 in Q2, which the company has said will be a single-arm, open-label trial with a natural history comparator. Investigators will track the therapy's impact on a biomarker-based composite endpoint that could pave the way for seeking accelerated approval.
Danon disease, a rare monogenic cardiomyopathy and multisystemic disorder, is caused by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene, which causes a deficiency in the eponymous protein. Due to this protein deficiency, patients develop severe progressive hypertrophic cardiomyopathy, left ventricular dysfunction, and arrhythmias. The median age of death for patients with the disease is 20 years old, Rossano said.
RP-A501 is an adeno-associated virus serotype 9 (AAV9) vector-based gene therapy that encodes a normal copy of a LAMP2B isoform transgene and is designed to restore protein expression. In the Phase I trial, investigators enrolled seven male patients with Danon disease who harbored pathogenic mutations in the LAMP2 gene, had hypertrophic cardiomyopathy, and received an intravenous infusion of RP-A501 at one of two doses.
Patients were enrolled into one of two age-specific cohorts: those 15 years of age or older and those between ages 8 and 14. They received prophylactic treatment with Genentech/Biogen's Rituxan (rituximab) and Pfizer's Rapamune (sirolimus) before the gene therapy infusion, but these were tapered after RP-A501 infusion.
"The immunosuppression protocol changed throughout the study course, which was informed by discussions with the FDA as well as ongoing safety data from this and other studies on AAV9 gene therapy," Rossano said.
While Pfizer has finished enrolling patients into the Phase I study, researchers are still conducting follow-up evaluations.
Before receiving an infusion of the gene therapy, all patients were classified as having Class II heart failure based on criteria from the New York Heart Association (NYHA), meaning that they experienced a slight limitation of physical activity. Based on endomyocardial biopsies, patients enrolled in the study also were not expressing LAMP2 at baseline.
One adult patient with left ventricular systolic dysfunction at baseline experienced progressive heart failure after treatment, which researchers said was related to disease progression and not the therapy. He required a heart transplant five months after treatment, at which point he no longer met study inclusion criteria.
Of the six remaining patients, all experienced benefits three years after RP-A501 infusion and their cardiac LAMP2B expression increased within six months of treatment. Five patients who were tracked for 18 months post-treatment stabilized or improved in left ventricular wall thickness and NYHA class. By comparison, in a prospective natural history study of untreated patients, no patients experienced improvements in NYHA class over 24 months.
All patients treated with RP-A501 had elevated B-type natriuretic peptide levels, a cardiac biomarker associated with heart failure, before infusion. After six months, researchers observed improved or stabilized B-type natriuretic peptide levels, suggesting improvement or stabilization of disease progression. The levels of those peptides worsened for untreated patients in the natural history study over 30 months.
All treatment-related adverse events were manageable and reversible, according to researchers. One adult in the high-dose cohort experienced thrombotic microangiopathy and renal failure requiring transient dialysis, which investigators deemed a serious adverse event, but this patient fully recovered. No serious adverse events have been observed in pediatric patients. "We did see a favorable safety profile with a low dose," Rossano said.
Ohio State University's AADC deficiency gene therapy
A gene therapy delivered directly into the brain of young patients suffering from a deficiency of the enzyme aromatic L-amino acid decarboxylase (AADC) greatly increased their motor function, according to Krystof Bankiewicz, director of the brain health and performance center at Ohio State University, who shared interim Phase I/II study findings on Thursday.
In the dose-escalation trial, investigators have treated 37 patients between 4 and 27 years old who have AADC deficiency: 17 based in the US and 20 in Poland. AADC deficiency is a rare genetic neurodevelopmental disorder caused by congenital deficiency of dopamine and serotonin. It presents in infancy and with a multitude of symptoms, including global developmental delay and autonomic dysfunction. Many of the symptoms are like those seen in Parkinson's disease patients, Bankiewicz said.
For the study, patients receive an adeno-associated virus serotype 2 vector-based gene therapy, which Bankiewicz referred to as AAV2-AADC. The gene therapy, designed to restore dopamine synthesis, delivers a copy of the DDC gene that encodes for AADC and is infused to multiple sites in a patient's midbrain through an MRI-guided surgical procedure.
"We have onset of gene expression pretty early on, within a month or so," Bankiewicz said. That's "how long it takes for the vector to encode and then start expressing."
An early sign of improvement for patients after treatment is change in oculogyric crisis (OGC), eye spasms that move patients' eyeballs into a fixed position. All patients experienced improvements in OGC, and the spasms completely resolved in 82 percent of patients, typically within a month, he said. However, in an interim analysis of 32 patients, three patients in whom these spasms initially disappeared saw the symptoms return after two years, though the episodes were mild, infrequent, and treatable.
Investigators are tracking multiple changes in patients' symptoms and motor function, using caregiver logs, neurologic examinations, and systematic reviews of home videos.
For patients who received treatment before 7 years old, all have attained head control — a substantial improvement for a population that had severe motor function impairment before treatment. Nearly 70 percent of older patients attained head control, according to Bankiewicz. About 80 percent of younger patients were able to sit independently one or two years after treatment, as were about half of older patients.
So far, five children who received the gene therapy have learned to walk independently, according to Bankiewicz.
Investigators also tracked changes in biomarkers such as dopamine production as measured by an analysis of cerebrospinal fluid homovanillic acid, which significantly increased for participants in the study.
There were three fatalities in the trial, representing a mortality rate consistent with the disease, according to Bankiewicz. None of the serious adverse events that arose during the trial were directly related to the neurosurgical procedure. Five patients had pneumonia that required hospitalization and three had symptomatic hypoglycemia, but investigators believe these adverse events are related to AADC deficiency rather than the gene therapy.
After infusion of a gene therapy designed to treat glycogen storage disease type Ia (GSDIa), patients have been able to taper or discontinue standard oral glucose replacement therapy, according to clinical trial data presented on Thursday.
Andrew Grimm, VP of global clinical development for metabolic diseases at Ultragenyx, presented data on patients with GSDIa who received the company's investigational gene therapy DTX401 in a first-in-human trial. GSDIa is an inherited metabolic disorder in which individuals are unable to produce normal glucose levels due to a deficiency of the enzyme glucose 6-phosphatase (G6Pase).
Patients suffering from GSDIa can become hypoglycemic and even progress to renal failure without a continuous source of glucose, often through daily use of oral glucose replacement therapy such as cornstarch. Patients might need to take a pound of cornstarch a day or more, according to Grimm, which can cause weight gain.
DTX401 is a liver-directed adeno-associated virus serotype 8 (AAV8) vector-based therapy that delivers a copy of the G6PC gene, which encodes G6Pase.
In the Phase I/II dose-escalation trial, investigators enrolled 12 patients with a confirmed diagnosis of GSDIa using molecular testing. Patients received a single intravenous infusion of DTX401 and oral steroid treatment for possible vector-induced hepatitis. Participation in the trial ran 52 weeks, but patients had the option to enroll in a long-term follow-up study for up to 260 weeks after treatment. All 12 patients remain in the follow-up portion of the trial, and the firm will continue to report updated efficacy and safety results, Grimm said.
A year after receiving the gene therapy, patients' average total daily cornstarch intake reduced 70 percent from baseline. Patients who received higher doses of the gene therapy experienced those reductions more quickly.
In the follow-up portion, patients' average total daily cornstarch intake reduced 65.6 percent from baseline to the last available time point. However, patient trajectories varied, with some needing increases in cornstarch intake after the first year, Grimm noted. Ultragenyx is still studying reasons for that increase in some patients, he said.
At one year, two-thirds of patients indicated that their disease was moderately or much improved since the start of the study.
No infusion-related or treatment-related serious adverse events were reported. All patients in the study experienced at least one treatment-emergent adverse event, such as hypertriglyceridemia and proteinuria. Seven patients experienced at least one treatment-emergent adverse event that was deemed serious based on a need for hospitalization, though none of those events were determined to be related to the study drug. No patients were discontinued from the study or died.
"We did see a number of serious adverse events, a lot of them related to underlying disease," Grimm acknowledged, noting that patients who receive the gene therapy will still need metabolic support and won't be able to discontinue glucose replacement immediately. "It still requires close monitoring of patients … and the cornstarch has to be titrated according to their degree of metabolic control."
Based on these initial results, Ultragenyx is testing its gene therapy in a randomized, placebo-controlled Phase III trial, which has finished enrolling patients. The company is expecting a data readout in the first half of 2024.
University of Massachusetts Chan School of Medicine's Tay-Sachs and Sandhoff disease gene therapy
In a Phase I study, six out of seven infants and juveniles with either Tay-Sachs or Sandhoff disease retained oral feeding ability for up to two years after receiving a two-vector gene therapy that uses rAAVrh8 capsids to express HexA and HexB.
Additionally, one patient preserved the ability to raise her head at 3 years old and one 14-month-old has begun to roll over. Both are developmental milestones that patients don't reach if they have Tay-Sachs and Sandhoff diseases, caused by HexA and HexB mutations, respectively.
The results of the study show "clear evidence of clinical benefit," and "suggested evidence of delayed onset seizure disorder," said Terry Flotte, dean of the Chan School of Medicine at the University of Massachusetts, who presented the data on Thursday.
The therapy also showed a favorable safety profile, Flotte said, with all patients managing immune suppression via the chemotherapy sirolimus, Genentech/Biogen's monoclonal antibody Rituxan (rituximab), and steroids. While investigators saw some anti-capsid immune response, Flotte said that they saw "no specific anti-transgene responses to either HexA or HexB at any appreciable level."
"The most notable issue that we had was that all three of the juvenile patients [enrolled in the study] experienced dystonia," Flotte said, "and did seem to be worsening over time."
In response to an audience question at the ASGCT meeting, Flotte commented that although his group has not yet seen HexA levels return to "typical" levels in study participants, this is a challenging outcome to measure, as there is no way to directly measure enzyme activity in brain tissue.
The gene therapy was administered as a single drug product with two components, where each component was manufactured in the same way and with the same lot release criteria, differing only in their respective bioactivity potency assays.
As such, "it is treated as one product," Flotte said, "and that will be an additional benefit of moving to a bicistronic construct in later studies."
Sarepta Therapeutics' SRP-9001
Four boys in the ambulatory phase of Duchenne muscular dystrophy (DMD) experienced functional physical improvements after receiving Sarepta Therapeutics' delandistrogene moxeparvovec and tolerated the recombinant adeno-associated viral vector-based gene transfer therapy well.
Delandistrogene moxeparvovec, previously known as SRP-9001, delivers to patients' muscle cells a shortened but functional dystrophin gene, which is missing or pathologically mutated in DMD.
The boys in Sarepta's Phase I/IIa open-label clinical trial received a single dose of SRP-9001. Researchers' main objective was to evaluate the therapy's safety and systemic delivery.
In addition to showing that the treatment was well tolerated, all boys, ages 4 to 6, showed clinically meaningful functional improvements at four years post-treatment. Specifically, all showed six-point improvements on the North Star Ambulatory Assessment (NSAA) functional grading scale during their first year following treatment. The year after, patients gained another point and remained stable.
Eleonora D'Ambrosio, a gene therapy fellow at Nationwide Children's Hospital and one of the study investigators, who presented the data at ASGCT, compared this result to the average three-point drop in NSAA scores seen in natural history studies over the same period.
SRP-9001-treated patients also showed improvements in functional assessments such as the four-stair climb, the 100-meter walk, and the 10-meter walk tests. D'Ambrosio highlighted that post-gene transfer therapy, patients showed a 60 percent mean improvement in the four-stair climb test.
D'Ambrosio also commented that the participants' body-mass indices were slightly lower for their age range than the population average, noting that a lower body mass index is associated with better responses to gene transfer.
Once study data had been collected, investigators compared participants' results to an external control group from a natural history study using a propensity score weighted system.
"[The] post hoc analysis allowed [us] to adjust for differences in particular aspects like age, NSAA score, time to rise from floor, and other outcomes, and the steroid use that could affect clinical findings and outcomes in Duchenne boys," D'Ambrosio said.
A comparison of NSAA scores over the four-year period between study participants and the natural history controls indicated a difference in mean change of 9.9 points from baseline.
"This study," D'Ambrosio said, "suggests durable expression of SRP-9001 … and provides a proof of concept for continued clinical trials."
BRL Medicine's BRL-101
Six patients with transfusion-dependent β-thalassemia (TDT), a rare disease characterized by reduced hemoglobin, achieved transfusion independence following a CRISPR-Cas9 therapy developed by BRL Medicine.
BRL-101, developed by the Shanghai, China-based drugmaker, disrupts the BCL11A erythroid enhancer, leading to reduced BCL11A expression and the induction of fetal gamma-globin, which is known to alleviate disease symptoms. As part of a Phase I/II trial ongoing in China, researchers edited CD34-positive hematopoietic stem and progenitor cells (HSPCs) from one girl and five boys, all between 5 and 15 years old. Patients had various beta-thalassemia phenotypes, but four of the six young patients had the most severe β0/β0 phenotype.
Patients' HSPCs underwent apheresis after mobilization, editing, and infusion back into each patient. Neutrophil implantation was achieved in all patients by approximately day 22 post-infusion, followed by platelet implantation by approximately day 78.
The edited HSPCs engrafted and differentiated into multiple lineages, which retained gene editing for at least two years following implantation. There was no evidence of off-target effects or of malignant clonal expansion.
"We also analyzed genes relevant to B-cell development and activation, and all genes related to B-cell generation and activation are similar across all samples," Bing Fu, the study's principal investigator said, referring to cells from healthy donors who were comparators and from pre- and post-treatment patients.
Furthermore, follow-up exams showed a CRISPR-Cas9 editing efficiency of over 60 percent.
Hemoglobin levels in all patients increased steadily and remained at healthy levels, and adverse events occurred with cell mobilization, apheresis, myeloablation, and autologous hematopoietic stem cell transplantation, all of which resolved quickly.
Four severe adverse events occurred, only one of which — a case of thrombocytopenia that has since resolved — was traced to BRL-101 treatment.
Two of the six patients have now been transfusion-independent for over three years. "BRL-101 has both an outstanding efficiency and safety profile," Fu said at the meeting.
He added that BRL Medicine and its academic collaborators have recently expanded their BRL-101 study to include young adults. In the first three for which there is data, investigators observed blood transfusion independence at one month, platelet implantation by three to four weeks, and neutrophil implantation by approximately two weeks.
BRL-101 in these young adults, Fu said, "is as good as, if not better than, in pediatric patients."